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Tissue Engineering of the Tendon/Ligament-To-Bone Transition

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Tissue Engineering of the Tendon/Ligament-To-Bone Transition Klinik und Poliklinik für Unfallchirurgie Fakultät für Medizin Tissue engineering of the tendon/ligament-to-bone transition Sònia Font Tellado Vollständiger Abdruck der von der Fakultät für Medizin der Technischen Universität München zur Erlangung des akademischen Grades eines Doktor der Naturwissenschaften (Dr. rer. nat.) genehmigten Dissertation. Vorsitzender: Prof. Dr. Dirk Busch Prüfer der Dissertation: 1. apl. Prof. Dr. Dr. Martijn van Griensven 2. Prof. Dr. Andreas Bausch Die Dissertation würde am 04.01.2018 bei der Technischen Universität München eingereicht und durch die Fakultät für Medizin am 04.07.2018 angenommen. 2 ABSTRACT The enthesis is a highly specialized interface tissue at the attachment sites of tendons/ligaments to bones. During musculoskeletal motion, a smooth transfer of mechanical stresses between tendons/ligaments (soft tissue) and bones (hard tissue) is possible due to the mechanical and structural gradients that compose the enthesis. Despite that, current surgical treatments for the repair of ruptured tendons and ligaments do not promote enthesis regeneration. This results in poor soft-to-hard tissue integration and high rupture recurrence rates, compromising long term clinical outcome. The present work proposes a novel strategy for enthesis regeneration based on the development of integrated tissue-engineered tendon/ligament-to-bone constructs (scaffolds). The constructs are composed of a region of anisotropic porosity (mimicking the aligned structure of the tendon/ligament) and a region of isotropic porosity (mimicking the non-aligned structure of bone/cartilage). The impact of fabrication parameters on the structural and mechanical properties of the constructs were evaluated and optimized to maximize pore sizes, mechanical stability, integration between the anisotropic and isotropic parts and biocompatibility. The tendon/ligament-to-bone constructs were functionalized with heparin to increase their ability to retain and deliver transforming growth factor beta 2 (TGF-β2) and growth/differentiation factor 5 (GDF5). The impact of structural features (pore morphology and alignment) and biological cues (growth factors) on cell behavior was evaluated in vitro with human primary adipose-derived mesenchymal stem cells (AdMSCs). Pore alignment influenced the cytoskeletal alignment and gene expression of AdMSCs, resulting in different gene expression patterns in the anisotropic and isotropic regions. In addition, pore alignment influenced the effect of growth factors on cell gene and protein expression. Synergistical effects between growth factors and pore alignment were identified, which selectively promoted the expression of tendon/ligament markers in the anisotropic part of the constructs, cartilage markers in the isotropic part and enthesis markers at the transition. Altogether, the data presented in this study improves current knowledge on how structural and biochemical cues provided by scaffolds can be tailored to induce specific multi-lineage differentiation of AdMSCs for tendon/ligament-to-bone regeneration. 3 ZUSAMMENFASSUNG Bei der Enthese handelt sich um ein hochspezialisiertes Gewebe am Übergang zwischen Sehnen/Bändern zu Knochen. Während der muskuloskelettalen Bewegung ist ein gleichmäßiger Transfer von mechanischen Stressimpulsen zwischen Sehnen/Bändern (Weichgewebe) zu Knochen (Hartgewebe) möglich, weil die Enthese aus bestimmten mechanischen und strukturellen Komponenten besteht. Dennoch unterstützen die gegenwärtig durchführbaren chirurgischen Behandlungsformen für die Wiederherstellung von gerissenen Bändern und Sehnen nicht die Heilung der Enthese. Das führt zu einer schlechten Integration der Übergänge zwischen harten und weichen Geweben und somit zu einer hohen Rate an erneuten Rupturen, die letztendlich das langfristige klinische Outcome beeinträchtigt. Die vorliegende Arbeit untersucht eine neuartige Strategie für die Regeneration der Enthese auf der Grundlage der Entwicklung von integrierten Sehnen/Bänder zu Knochen Konstrukten (Scaffolds), die mittels Tissue Engineering hergestellt werden. Die Konstrukte bestehen aus einem Teil mit anisotroper Porosität (der die parallel angeordnete Porenstruktur der Sehnen/Bänder imitiert) und einem Teil mit isotroper Porosität (der die zufällig angeordnete Porenstruktur der Knochen/Knorpel imitiert). Der Einfluss der Herstellungsparameter auf die strukturellen und mechanischen Eigenschaften der Konstrukte wurde untersucht und optimiert, um die Porengrößen, die mechanische Stabilität und die Integration zwischen den anisotropen und isotropen Teilen und deren Biokompatibilität zu maximieren. Die Sehnen/Bänder zu Knochen Konstrukte wurden mit Heparin funktionalisiert, um ihre Fähigkeit zu verbessern, Transforming Growth Factor beta 2 (TGF-β2) und Growth/Differentiation Factor 5 (GDF5) zu speichern und abzugeben. Der Einfluss der strukturellen (Morphologie und Ausrichtung der Poren) und biologischen Eigenschaften (Wachstumsfaktoren) auf das Verhalten der Zellen wurde in vitro mittels humaner primärer, mesenchymaler Stammzellen untersucht, die aus dem Fettgewebe gewonnen wurden (AdMSCs). Die Ausrichtung der Poren beeinflusste die zytoskelettale Ausrichtung und die Genexpression der AdMSCs, was unterschiedliche Genexpressionsmuster in den anisotropen und isotropen Teilen zur Folge hatte. Zusätzlich beeinflusste die Ausrichtung der Poren den Effekt der Wachstumsfaktoren auf die Expression von Genen und Proteinen in den Zellen. Wir fanden auch synergistische Effekte zwischen Wachstumsfaktoren und der Ausrichtung der Poren, die gezielt die Expression von Sehnen/Bänder Markern im anisotropen Teil des Konstrukts, von Knorpelmarkern im isotropen Teil und von Enthesemarkern im Übergangsbereich steigerten. 4 Insgesamt erweitern die durch diese Studie gewonnenen Erkenntnisse das Wissen, wie strukturelle und biochemische Eigenschaften von Scaffolds so maßgeschneidert werden können, dass eine spezifische multipotente Differenzierung von AdMSCs für die Regeneration des Sehnen/Bänder zu Knochen Übergangs erreicht wird. 5 TABLE OF CONTENTS i ABSTRACT .............................................................................................................................. 3 ii ZUSAMMENFASSUNG ........................................................................................................... 4 1. ABBREVIATIONS ................................................................................................................ 10 2. INTRODUCTION .................................................................................................................. 12 2.1 The tendon/ligament-to-bone interface (enthesis) .......................................................... 12 2.1.1 Enthesis structure and composition .................................................................... 13 2.1.2 Enthesis development ........................................................................................ 14 2.1.3 Mechanical properties of the enthesis ................................................................ 17 2.2 Strategies to engineer the tendon/ligament-to-bone interface ........................................ 18 2.2.1 Biomaterials and scaffolds .................................................................................. 18 2.2.2 Cells ................................................................................................................... 21 2.2.3 Biochemical cues: growth factors ....................................................................... 22 2.2.4 State of the art on tendon/ligament-to-bone tissue engineering .......................... 24 2.3 Evaluation of tissue engineered tendon/ligament-to-bone constructs ............................. 25 2.3.1 Markers of cell phenotype and tissue-specific ECM ............................................ 26 2.3.2 Mechanical parameters ...................................................................................... 28 2.4 Aims and experimental approach ................................................................................... 28 3. MATERIALS & METHODS ................................................................................................... 30 3.1 Silk fibroin extraction and processing ............................................................................. 30 3.2 Fabrication of anisotropic scaffolds ................................................................................ 31 3.3 Fabrication of isotropic scaffolds .................................................................................... 32 3.4 Fabrication of biphasic scaffolds .................................................................................... 33 3.5 Scaffold characterization ................................................................................................ 34 3.5.1 Fourier transform infrared spectroscopy (FTIR) .................................................. 34 3.5.2 Digital light microscopy ....................................................................................... 35 6 3.5.3 Field-Emission Scanning electron microscopy (FESEM) .................................... 35 3.5.4 Micro-computed tomography (µCT) .................................................................... 35 3.5.5 Permeability ....................................................................................................... 36 3.5.6 Mechanical testing .............................................................................................. 36 3.6 Functionalization of
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